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830 Evidence of Microangiopathy in Children with Sars-Cov-2 Regardless of Clinical Presentation

Program: Oral and Poster Abstracts
Session: 301. Vascular Wall Biology, Endothelial Progenitor Cells, and Platelet Adhesion, Activation, and Biochemistry: Poster I
Hematology Disease Topics & Pathways:
Coronaviruses, SARS-CoV-2/COVID-19, viral, Diseases, Bleeding and Clotting, Infectious Diseases, Clinically relevant, Thrombotic Disorders
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Caroline Diorio, MD1, Kevin O McNerney, MD, MSTR2*, Michele P. Lambert, MD, MSTR3, Michele Paessler, D.O.4*, Julie Chase, MD, PhD5*, Kandace Gollomp, MD6, Benjamin L Laskin, MD7*, Laura A Vella, MD, PhD8*, Sarah E Henrickson, MD PhD5*, Emily Liebling, MD5*, Chakkapong Burudpakdee, BS9*, Jessica Lee, BS10*, Fran Balamuth, MD PhD11*, Allison M Blatz, MD5*, Kathleen Chiotos, MD, MSCE12*, Julie C Fitzgerald, MD13*, Therese Giglia, MD, MSCE14*, Audrey R Odom John, MD PhD5*, Whitney Petrosa, CPNP9*, Kathleen Sullivan, MD, PhD15*, Char M Witmer, MD16, Hamid Bassiri, MD/PhD5*, Edward M Behrens, MD5* and David T. Teachey, MD17

1Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
2Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
3Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
4Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
5Children's Hospital of Philadelphia, Philadelphia, PA
6Department of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
7Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA
8Infectious Disease, Children's Hospital of Philadelphia, Philadelphia, PA
9Immune Dysregulation Frontier Program, Children's Hospital of Philadelphia, Philadelphia, PA
10Immune Dysregulation Frontier Program, Children's Hospital Philadelphia, Philadelphia, PA
11Division of Emergency Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
12Division of Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
13Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
14Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA
15Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA
16Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA
17Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and The Perelman School of Medicine at The University of Pennsylvania, Rutledge, PA

Introduction: During the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), 3 distinct phenotypes have emerged in children. The majority of children have mild or no symptoms. Similar to adults, a minority of children can be severely affected with respiratory distress requiring intensive care. Finally, they may develop a phenomenon presumed unique to children termed Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a hyperinflammatory syndrome characterized by fever and organ dysfunction (particularly cardiac) in the setting of recent COVID-19 infection. Reports from the adult literature have invoked thrombotic microangiopathy (TMA) and complement activation as a potential cause for severe manifestations of COVID-19 (Zhang et al. NEJM. 2020; Campbell et al. Circulation 2020). Soluble C5b9 (sC5b-9), the terminal complement complex, has been implicated as a marker of hematopoietic stem cell transplant associated TMA (HSCT-TMA; Jodele et al. Blood 2014). We sought to elucidate the role of terminal complement activation and TMA in the different pediatric disease phenotypes.

Methods: We enrolled children admitted to the Children’s Hospital of Philadelphia during the COVID-19 pandemic who had evidence of SARS-CoV-2 infection on reverse transcriptase polymerase chain reaction (RT-PCR) from mucosa, or met clinical criteria for MIS-C. Patients (pts) were classified in to 3 categories: minimal COVID-19 symptoms or incidental finding of SARS-CoV-2 infection, severe COVID-19 requiring ventilatory support, or MIS-C. To investigate the role of TMA in children with COVID-19 we measured sC5b-9 in plasma of pts with the 3 manifestations of SARS-CoV-2, and in healthy controls. sC5b9 was measured in triplicate at two dilutions by ELISA. Proinflammatory cytokines were measured using V-Plex Pro-inflammatory Panel 1 Human Kits and analyzed on a QuickPlex SQ120. P-values were computed using Dunn’s multiple comparisons test after Kruskal-Wallis testing. Blood smears were examined by a hematologist and hematopathologist for schistocytes.

Results: 50 pts were enrolled on whom complete sC5b9 data were available: minimal COVID-19 (N=18), severe COVID-19 (N=11), and MIS-C (N=21). Plasma was obtained on healthy controls (N=26). The median sC5b9 level in healthy controls (57 ng/mL) differed significantly (p<0.001 in each case; Figure 1A) from that in pts with minimal disease (392 ng/mL), severe disease (646 ng/mL), and MIS-C (630 ng/mL); differences between MIS-C, minimal, and severe were not statistically significant. Elevations in sC5b9 correlated in a statistically significant manner with the maximum creatinine and blood urea nitrogen (BUN) measured during hospitalization (Figure 1B&C), but not age (p=0.512). sC5b9 did not correlate with lactate dehydrogenase (LDH), nor with the lowest levels of fibrinogen, hemoglobin or platelet counts. Of pts with available data, 19/26 (73.1%) had elevated LDH, 2/31 (6.4%) had hypofibrinogenemia, 35/47 (74.5%) were anemic, and 28/47 (59.6%) were thrombocytopenic.

Pro-inflammatory cytokines were measured. Of particular interest to TMA is the neutrophil chemotactic factor IL-8, because of its role as a marker of endothelial damage (Dvorak et al. Front Pediatr 2019). Levels of IL-8 differed significantly between pts with MIS-C (p=0.0166) or pts with severe COVID-19 (p=0.0079), when compared to minimal COVID-19 pts; but not between pts with MIS-C and severe disease (p = 0.99).

Blood smears were available on 34 patients. Schistocytes were present in 13/15 (87%) patients with MIS-C, 7/8 (87%) patients with severe COVID-19 and 5/11 (45%) patients with minimal COVID-19 (χ2=6.59, p=0.037).

Conclusions: We demonstrate derangements of the final common pathway of complement activation in children with the 3 presentations of SARS-CoV-2. Strikingly, sC5b9s were abnormal even in children with minimal disease or incidental infection. Renal dysfunction correlated with elevations in sC5b9, strengthening the evidence that TMA plays a role in the pathophysiology of SARS-CoV-2 infection. Future work is aimed at further characterizing the role of the complement cascade in the pathogenesis of MIS-C and COVID-19 in children. The long-term complications of endothelial damage and complement activation are unknown and extended follow-up is warranted.

Disclosures: Diorio: Children's Hospital of Philadelphia: Research Funding; University of Pennsylvania: Research Funding. Lambert: 22qSociety: Consultancy; RDMD ITP study: Consultancy; Octapharma: Consultancy, Research Funding; Educational Concepts in Medicine: Consultancy; Shionogi: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenix: Consultancy; CdLS Foundation: Consultancy; Sysmex: Research Funding; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia: Consultancy, Membership on an entity's Board of Directors or advisory committees; ClinGen: Honoraria; Platelet Disorder Support Association (PDSA): Consultancy; AstraZeneca: Research Funding; Bayer: Consultancy; ITP Australia: Consultancy. Henrickson: Horizon Pharma: Other: ad hoc board meeting. Odom John: Burroughs Wellcome: Research Funding; NIAID: Research Funding. Bassiri: CSL Behring: Other: Spouse receives stocks . Behrens: NIH/NIAID: Research Funding. Teachey: Janssen: Consultancy; Amgen: Consultancy; La Roche: Consultancy; Sobi: Consultancy.

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